The ethics of research involving animals - Nuffield Council on ...

T h e e t h i c s o f r e s e a r c h i n v o l v i n g a n i m a l s
approaches is illustrated by a decrease in rabbit eye tests in the UK from approximately
4,000 in 1995 to 1,100 in 2003. 6
9.13 Acute systemic toxicity is assessed by the administration <strong>of</strong> a single dose <strong>of</strong> compound, typically
to rats and mice, orally, dermally or by inhalation. For pharmaceuticals, the main aims <strong>of</strong> these
studies are to determine the nature (including delayed toxicity) and duration <strong>of</strong> any acute toxic
response. <strong>The</strong>y also determine the maximum non-lethal dose and provide preliminary
information relevant to single exposure or over-dosage in humans (see paragraph 9.39). 7
9.14 For industrial chemicals and agrochemicals, testing covers acute toxicity by oral, dermal and
inhalation routes <strong>of</strong> exposure. <strong>The</strong> information obtained is used primarily to ascribe a chemical
to bands <strong>of</strong> acute toxic effect, which restricts how the materials may be used, and thus the
extent <strong>of</strong> human exposure by the routes <strong>of</strong> exposure which have been evaluated. In the past,
in the UK and elsewhere, acute systemic toxicity was investigated by the use <strong>of</strong> lethal-dose
tests, in which the oral dose causing the death <strong>of</strong> 50 percent <strong>of</strong> the treated <strong>animals</strong> (the LD 50
value) was determined. 8 Such tests used at least 30 <strong>animals</strong> per test chemical and required
death <strong>of</strong> the <strong>animals</strong> as an endpoint, regardless <strong>of</strong> the suffering caused. In 2001 the OECD
agreed that the LD 50 test for acute oral toxicity should be abolished and deleted from the
OECD manual <strong>of</strong> internationally accepted test guidelines by the end <strong>of</strong> 2002 (see paragraphs
9.4 and 12.8). 9 Several alternative methods have been developed which use fewer <strong>animals</strong> and
in some cases replace death as the endpoint with signs <strong>of</strong> significant toxicity instead.
Information on similar chemicals is used to guide the selection <strong>of</strong> initial dose levels and the
tests are designed to avoid or minimise lethality or severe toxicity. <strong>The</strong>se methods have
replaced the LD 50 test for acute oral toxicity, but several acute tests such as those <strong>involving</strong>
inhalation, dermal and eye exposure have yet to be modified. <strong>The</strong>y are still used
internationally for tests on birds and, for some purposes, also on mammals. 10 Lethal-dose tests
are also still used to assess the safety <strong>of</strong> biological products, such as vaccines (Box 8.5), and
certain foods, such as shellfish, for the presence <strong>of</strong> toxins (see paragraph 9.37).
CHAPTER 9 ANIMAL USE IN TOXICITY STUDIES
9.15 <strong>The</strong> approach to assessing the acute toxicity <strong>of</strong> pharmaceuticals differs from that described
above, in that maximum tolerated dose (MTD) studies are carried out to aid the later process
<strong>of</strong> dose selection. <strong>The</strong>se tests <strong>of</strong>ten replace acute studies, especially in the case <strong>of</strong> larger
species such as the dog and primates which are used to complement and verify earlier
findings in rodents. <strong>The</strong>y involve steadily increasing the dose given to an animal (single or a
number <strong>of</strong> consecutive doses), until adverse effects indicate that an MTD has been reached.
This is normally determined by careful observation <strong>of</strong> the <strong>animals</strong>, but there is no universally
accepted definition <strong>of</strong> the MTD and effects such as vomiting and convulsions may occur and
are sometimes used as signs <strong>of</strong> the MTD (see paragraphs 9.34–9.45).
6 See Home Office (2004) Statistics <strong>of</strong> Scientific Procedures on Living Animals Great Britain 2003 (Norwich: HMSO).
7 <strong>The</strong> studies provide information that may support selection <strong>of</strong> dose levels for repeated-dose toxicity studies, in vivo
genotoxicity tests (see paragraphs 9.20-9.21) and, subsequently, first human exposure studies.
8 <strong>The</strong> OECD gives the definition as the dose that can be expected to cause death in 50 percent <strong>of</strong> <strong>animals</strong> when administered
by the oral route.
9 OECD (2001) OECD Test Guideline 401 will be deleted: A Major Step in Animal Welfare: OECD Reaches Agreement on the
Abolishment <strong>of</strong> the LD 50 Acute Toxicity Test, available at:
http://www.oecd.org/document/52/0,2340,en_2649_34377_2752116_1_1_1_1,00.html. Accessed on: 27 Apr 2005; <strong>The</strong> UK ceased
the practice <strong>of</strong> the LD 50 test in 1999 (APC (1999) Press release: LD 50 Test - Changes To Licensing Procedures, available at:
http://www.apc.gov.uk/press_releases/991021.htm. Accessed on: 27 Apr 2005). In the US, Environmental Protection Agency
guidelines describe the LD 50 test as standard for pesticides and toxic substances although state that it may be unnecessary in
certain circumstances (Environment Protection Agency (1998) Health Effects Test Guidelines OPPTS 870.1100
Acute Oral Toxicity, available at: http://www.epa.gov/docs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-
1100.pdf. Accessed on: 27 Apr 2005.
10 OECD (2002) OECD guidelines for the testing <strong>of</strong> chemicals: Proposal for a new guideline 223 – Avian acute oral toxicity test,
available at: http://www.oecd.org/dataoecd/16/41/1836204.pdf. Accessed on: 27 Apr 2005.
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